Pramipexole is a known dopamine D2 receptor agonist. It is structurally different from the ergot-derived drugs, e.g., bromocriptine or pergolide. It is also pharmacologically unique in that it is a full agonist and has receptor selectivity for the dopamine D2 family of dopamine receptors.
Pramipexole is designated chemically as (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole and has the molecular formula C10H17N3S and a relative molecular mass of 211.33. The chemical formula is as follows:

The salt form commonly used is pramipexole dihydrochloride monohydrate (molecular formula C10H21Cl2N3OS; relative molecular mass 302.27). Pramipexole dihydrochloride monohydrate is a white to off-white, tasteless, crystalline powder. Melting occurs in the range of 296° C. to 301° C., with decomposition. Pramipexole is a chiral compound with one chiral center. Pure (S)-enantiomer is obtained from the synthetic process by chiral recrystallization of one of the intermediates during synthesis.
Pramipexole dihydrochloride monohydrate is a highly soluble compound. Water solubility is more than 20 mg/mL and solubility in buffer media is generally above 10 mg/ml, between pH 2 and pH 7.4. Pramipexole dihydrochloride monohydrate is not hygroscopic, and has a highly crystalline nature. Under milling, the crystal modification (monohydrate) does not change. Pramipexole is very stable in the solid state, yet in solution it is light sensitive.
Pramipexole immediate release (IR) tablets were first authorized in the USA in 1997, followed over the course of the next years by marketing authorizations in the European Union (EU), Switzerland, Canada, and South America as well as in countries in Eastern Europe, the Near East, and Asia.
Pramipexole IR tablets are indicated in the EU and US for the treatment of signs and symptoms of either early Parkinson's Disease or advanced Parkinson's Disease in combination with levodopa. The IR tablets have to be taken 3 times a day.
From the pharmacokinetic point of view, pramipexole IR tablets are rapidly and completely absorbed following oral administration. The absolute bioavailability is greater than 90% and the maximum plasma concentration occurs within 1 to 3 hours. The rate of absorption is reduced by food intake but not the overall extent of absorption. Pramipexole shows linear kinetics and a relatively small inter-patient variation of plasma levels. The elimination half-life (t1/2[h]) varies from 8 hours in the young to 12 hours in the elderly.
As is commonly known, modified release of active ingredient(s) allows simplification of the patient's administration scheme by reducing the amount of recommended daily intakes, improves patient's compliance, and attenuates adverse events, e.g., related to high plasma peaks. Modified release pharmaceutical preparations regulate the release of the incorporated active ingredient or ingredients over time and comprise formulations with a controlled, a prolonged, a sustained, a delayed, a slow or an extended release, so they accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions or promptly dissolving dosage forms.
A modified or extended release of active ingredient(s) from a pharmaceutical preparation may be accomplished by homogeneously embedding the active ingredient(s) in a hydrophilic matrix, being a soluble, partially soluble or insoluble network of viscous, hydrophilic polymers, held together by physical or chemical entanglements, by ionic or crystalline interactions, by complex formation, by hydrogen bonds or van der Waals forces. The hydrophilic matrix swells upon contact with water, thereby creating a protective gel layer from which the active ingredient(s) are slowly, gradually, continuously released in time either by diffusion through the polymeric network, by erosion of the gel layer, by dissolution of the polymer, or by a combination of these release mechanisms.
However, it has proved difficult to formulate a dosage form having a suitable combination of modified, extended, or sustained-release and handling properties, where the drug is one having relatively high solubility, as in the case of pramipexole dihydrochloride.
There are a number of approaches described in prior art to provide controlled release pharmaceutical compositions of pramipexole.
WO 2004/010997 describes a sustained-release pharmaceutical composition in a form of an orally deliverable tablet comprising a water-soluble salt of pramipexole, dispersed in a matrix comprising a hydrophilic polymer and a starch having a tensile strength of at least about 0.15 kN cm−2, preferably at least about 0.175 kN cm−2, and more preferably at least about 0.2 kN cm−2, at a solid fraction representative of the tablet. The disclosure thereof is concentrated to provide a composition with sufficient hardness yield during a high-speed tabletting operation, in particular to resist erosion during application of a coating layer. According to a preferred embodiment it is provided a pharmaceutical composition in a form of an orally deliverable tablet having a core comprising pramipexole dihydrochloride monohydrate in an amount of about 0.375, 0.75, 1.5, 3, or 4.5 mg, dispersed in a matrix comprising (a) HPMC type 2208 in an amount of about 35% to about 50% by weight of the tablet and (b) a pregelatinized starch having a tensile strength of at least about 0.15 kN cm−2 at a solid fraction of 0.8, in an amount of about 45% to about 65% by weight of the tablet; said core being substantially enclosed in a coating that constitutes about 2% to about 7% of the weight of the tablet, said coating comprising an ethyl cellulose-based hydrophobic or water-insoluble component and an HPMC-based pore-forming component in an amount of about 10% to about 40% by weight of the ethyl cellulose-based component.
Furthermore, WO 2004/010999 discloses an orally deliverable pharmaceutical composition comprising a therapeutically effective amount of pramipexole or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, said composition exhibiting at least one of (a) an in vitro release profile wherein on average no more than about 20% of the pramipexole is dissolved within 2 hours after placement of the composition in a standard dissolution test; and (b) an in vivo pramipexole absorption profile following single dose oral administration to healthy adult humans wherein the time to reach a mean of 20% absorption is greater than about 2 hours and/or the time to reach a mean of 40% absorption is greater than about 4 hours. However, in practical use, it appears that any formulation having a modified or controlled release profile designed for a once daily application would meet the above requirements for which a general teaching how to adjust such a profile is missing. All examples are directed to tablets and not to coated pellets.
Absorption profile in vivo with matrix systems is frequently highly variable due to differences in gastrointestinal transit times. Multiparticle extended release formulations such as pellets distribute in the gastrointestinal tract and therefore show reduced variability in rate and extent of absorption. Furthermore different dose strengths can be achieved easily by filling different amounts of the same extended release pellet type into capsules. As reproducible absorption is mandatory with pramipexole and there is a wide range of therapeutic dose strengths, these properties offer considerable advantages of pramipexole extended release pellets over the predescribed examples mentioned above.
Therefore, it is an object of the present invention to provide an extended release pellet formulation of pramipexole or a pharmaceutically acceptable salt thereof which may be filled in a capsule and is suitable for once-daily oral administration. It is a further object to provide a pellet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof which may be filled in a capsule and is suitable to provide a day-long therapeutic effect and will allow patients to treat their symptoms with a single daily dose, and makes it possible to adjust the release profile of the active ingredient according to a selected release profile dependent or independent from the pH value. Furthermore, a method of manufacturing the pellet formulation shall be provided.